Gamida Cell Phase 3 Study Design Outline Approved by FDA and EMA

Gamida Cell, a cell therapy company based in Jerusalem, Israel, has reached agreements with the US Food and Drug Administration (USFDA) and the European Medicines Agency (EMA) with regards to a Phase III study design outline for testing their NiCord product. NiCord is a blood cancer treatment derived from a single umbilical cord blood until expanded in culture and enriched with stem cells by means of the company’s proprietary NAM technology.

Gamida Cell is moving forward now with plans to commence an international, multi-center, Phase III study of NiCord in 2016. Phase I/II data of 15 patients are expected in the fourth quarter of 2015. NiCord is in development as an experimental treatment for various types of blood cancers including Acute Myeloid Leukemia (AML), Acute Lymphoblastic Leukemia (ALL), Myelodysplastic Syndrome (MDS), and Chronic Myelogenous Leukemia (CML).

NiCord® is derived from a single cord blood unit which has been expanded in culture and enriched with stem cells using Gamida Cell’s proprietary NAM technology. NAM technology proceeds from the observation that nicotinamide, a form of vitamin B3, inhibits the loss of functionality that usually occurs during the culture process of umbilical cord blood stem cells, when added to the culture medium. Pre-clinical studies have also shown that the expanded cell grafts manufactured using NAM technology demonstrate improved functionality following infusion in a living animal. These stem cells show improved movement, home to the bone marrow, and show higher rates of engraftment, or durable retention in the bone marrow. Based on these results, Gamida Cell is currently testing in clinical trials (in patients) cells expanded in culture with the NAM platform to determine their safety and effectiveness as a treatment for blood cancers, sickle-cell anemia and thalassemia. NiCord is intended to fill the crucial clinical need for a treatment for the vast majority of blood cancer patients indicated for bone marrow transplantation, with insufficient treatment options. This segment has a multi-billion dollar market potential.

“The FDA and EMA feedback is a major regulatory milestone for NiCord. NiCord is a life-saving therapy intended to provide a successful treatment for the large number of blood cancer patients who do not have a family related matched donor. Gamida Cell is dedicated to changing the paradigm in transplantation by bringing this therapy to market as soon as possible,” said Dr. Yael Margolin, president and CEO of Gamida Cell.

“The positive regulatory feedback confirms that Gamida Cell’s NiCord program is on a clear path to approval both in the U.S. and EU. We look forward to continuing the development of this very important product in cooperation with sites of excellence in cord blood transplantation worldwide,” said Dr. David Snyder, V.P. of Clinical Development and Regulatory Affairs at Gamida Cell.

The Phase III study will be a randomized, controlled study of approximately 120 patients. It will compare the outcomes of patients transplanted with NiCord to those of patients transplanted with un-manipulated umbilical cord blood.


Enzyme Promotes Cancer Stem Cell Growth in Chronic Myeloid Leukemia

An international research team led by researchers at the University of California, San Diego School of Medicine has identified an enzyme that plays a key role in cancer stem cell reprogramming in a blood-based cancer known as chronic myeloid leukemia (CML).

CML treatment has received a tremendous boost by the discovery and development of chemotherapuetic agents known as tyrosine kinase inhibitors. Tyrosine kinase inhibitors attack a very specific group of signaling molecules that go awry in CML, and because of their high degree of specificity, these drugs are well tolerated and rather effective.


Tyrosine kinase inhibitors or TKIs block receptors called receptor tyrosine kinases that bind growth factors. Such receptors include molecules like Epidermal Growth Factor Receptor, which binds the growth factor EGF (Epidermal Growth Factor), Plate-Derived Growth Factor Receptor, which binds Platelet-Derived Growth Factor, and several others. Receptor tyrosine kinases are proteins that are embedded in the membrane of cells and when they are engaged by a specific growth factor, they pair up with another molecule and bind the growth factor tightly. Because this binding of their growth factor targets pairs two receptor tyrosine kinases together, the portion of the receptor protein that sticks toward the inside of the cell is activated. This internal portion of the receptor has “kinase” activity. Kinases are enzymes that stick phosphate groups on other molecules. Kinases place their phosphate groups on very specific targets. In the case of receptor tyrosine kinases, the target is the amino acid tyrosine. It just so happens that the internal piece of receptor tyrosine kinases contains several tyrosine residues and the paired receptors molecules tag each other with several phosphate groups on their tyrosines.

EGF activity

Phosphotyrosine acts as a signal to the inside of the cell, because specific protein contain pieces that can bind to phosphotyrosine. These phosphotyrosine-binding proteins (SH2-domain proteins for those who care about such things) drag powerful signaling molecules to the cell membrane. These signaling molecules are activated and the cell undergoes changes that cause it to move, growth, divide, or do other types of things.

EGFR signaling

In the case of blood cells, activation of particular receptor tyrosine kinases induces cells to grow and divide. Because there are exquisite controls on the signals set in motion by tyrosine, these signals cells divide and then stop. However, if the genes that encode these receptor tyrosine kinases undergo mutations that allow the receptors to pair up without binding growth factors, then the receptors will activate themselves at will without being dependent on the availability of growth factors. Cell will grow uncontrollably and fill up the bone marrow and blood.

At this point, we can see how TKIs work. These small molecules bind to the kinase part of receptor tyrosine kinases and gum them up. Because cells do not receive the signal to grow, they stop growing uncontrollably and this send the cancer into remission. TKIs include such famous drugs as Gleevec (imatinib), which was one of the first TKIs and has provent very successful against CML. However, after long periods of time on Gleevec, tumor cells can become resistant to it, and the physician must change drugs. Other TKIs include gefitinib (Iressa), and erlotinib (Tarceva), which inhibit Epidermal Growth Factor Receptor, Lapatinib (Tykerb), which is a dual inhibitor of EGFR and a subclass called Human EGFR type 2, and Sunitinib (Sutent) which is multi-targeted drug that inhibits Platelet-Derived Growth Factor Receptor and Vascular Endothelial Growth Factor Receptor.











There are also other most specialized TKIs such as sorafenib (Nexavar), which targets a complex pathway that leads to a kinase signaling cascade, and nilotinib (Tasinga) which inhibits the fusion protein bcr-abl and is typically prescribed when a patient has shown resistance to imatinib (Gleevex).

Well, with all these new drugs, what’s the problem? The problem is that blood cancers, leukemias, can find ways around these treatments. Therefore, we must learn more these cancers in order to improve treatment of them. Leukemias are definitely tumors that emerge from cancer stem cells. Therefore, if you kill the cancer stem cells, you kill the tumor.

Principle investigator of this research, Catriona Jamieson, associate professor of medicine at UC San Diego, in collaboration with colleagues from Canada and Italy reported that inflammation, a phenomenon long associated with the development of cancer, increases the activity of the enzyme ADAR1 or adenosine deamiinase 1.

ADAR1 is expressed during embryonic development and it is essential in blood cell development. After embryonic development, ADAR1 switches off, but is reactivated by viral infections. Its role during viral infections is to protect blood cell-making stem cells from viral attacks. In leukemia stem cells, however, ADAR1 enhances the abnormal processing of RNA molecules. This causes enhanced cell renewal and resistance of malignant stem cells to chemotherapy.

Jamieson has already studied the link between cancer stem cell instability and abnormal RNA processing. She said, “People normally think about DNA instability in cancer, but in this case, it’s how the RNA is edited by enzymes that really matters in terms of cancer stem cell generation and resistance to conventional therapy.”

Because this RNA processing process is basic to cells and occurs in closely related organisms as well, studying it should be possible in model systems. It also represents a novel target for new therapies. According to Jamieson, inflammation is “an essential driver of cancer relapse and therapeutic resistance.”

Jamieson continued, “ADAR1 is an enzyme that we may be able to specifically target with a small molecule inhibitor, an approach we have already used effectively with other inhibitors. If we can block the capacity of leukemia stem cells to use ADAR1, if we can knock down that pathway, maybe we can put stem cells back on the right track and stop malignant cloning.”

The initiation of CML requires a mutation that fuses two genes together. One of these genes, BCR, fuses to a protein tyrosine kinase called ABL to generate the BCR-ABL gene that makes a fusion protein with uninhibited activity. The white blood cells that contain the BCR-ABL fusion protein expand slowly. The slowness with which this leukemia expands makes it difficult to diagnose early, and diagnosis is only possible once there are large numbers of precursors and malignant cells throughout the bloodstream and bone marrow. The median age at which CML is diagnosed is 66, and despite the advances in chemotherapeutic treatments, the vast majority of patients relapse if therapy is discontinued, since the cancer stem cells are dormant and resistant to treatment. If ADAR1 is addressed as a target, then perhaps treatments that target ADAR1 will overcome cancer stem cell resistance and prevent relapse.

Formation of the Philadelphia chromosome that produces the bcr-abl oncogene.
Formation of the Philadelphia chromosome that produces the bcr-abl oncogene.

In the United States alone, there are an estimated 70,00 people with CML and as the population ages, the prevalence of this disease is projected to jump to approximately 181,000 by 2050.

See “ADAR1 promotes malignant progenitor reprogramming in chronic myeloid leukemia.” Qingfei Jianga et al., PNAS DOI: 10.1073/pnas.2123021110.